The present invention relates to novel azetidin compounds. The compounds possess valuable therapeutic properties and are particularly suitable, for treating diseases that respond to modulation of the serotonin 5-HT6 receptor.
Serotonin (5-hydroxytryptamine, 5-HT), a monoamine neurotransmitter and local hormone, is formed by the hydroxylation and decarboxylation of tryptophan. The greatest concentration is found in the enterochromaffin cells of the gastrointestinal tract, the remainder being predominantly present in platelets and in the Central Nervous System (CNS). 5-HT is implicated in a vast array of physiological and pathophysiological pathways. In the periphery, it contracts a number of smooth muscles and induces endothelium-dependent vasodilation. In the CNS, it is believed to be involved in a wide range of functions, including the control of appetite, mood, anxiety, hallucinations, sleep, vomiting and pain perception.
Neurons that secrete 5-HT are termed serotonergic. The function of 5-HT is exerted upon its interaction with specific (serotonergic) neurons. Until now, seven types of 5-HT receptors have been identified: 5-HT1 (with subtypes 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E and 5-HT1F), 5-HT2 (with subtypes 5-HT2A, 5-HT2B and 5-HT2c), 5-HT3, 5-HT4, 5-HT5 (with subtypes 5-HT5A and 5-HT5B), 5-HT6 and 5-HT7. Most of these receptors are coupled to G-proteins that affect the activities of either adenylate cyclase or phospholipase Cγ.
The human 5-HT6 receptors are positively coupled to adenylyl cyclase. They are distributed throughout the limbic, striatal and cortical regions of the brain and show a high affinity to antipsychotics.
The modulation of the 5-HT6 receptor by suitable substances is expected to improve certain disorders including cognitive dysfunctions, such as a deficit in memory, cognition and learning, in particular associated with Alzheimer's disease, age-related cognitive decline and mild cognitive impairment, attention deficit disorder/hyperactivity syndrome, personality disorders, such as schizophrenia, in particular cognitive deficits related with schizophrenia, affective disorders such as depression, anxiety and obsessive compulsive disorders, motion or motor disorders such as Parkinson's disease and epilepsy, migraine, sleep disorders (including disturbances of the Circadian rhythm), feeding disorders, such as anorexia and bulimia, certain gastrointestinal disorders such as Irritable Bowl Syndrome, diseases associated with neurodegeneration, such as stroke, spinal or head trauma and head injuries, such as hydrocephalus, drug addiction and obesity.
Compounds having an affinity for the 5-HT6 receptor have been described in the prior art, e.g. in WO 2007/006677, WO 2007/004959, WO 2006/081332, WO 2006/062481, WO 2005/037834, WO 2005/026125, WO 00/05225 and WO 98/27081.
WO 01/05758 discloses compounds of the following formula,
wherein B, D and W are nitrogen or CH, Z is nitrogen or a substituted carbon atom, A is a radical containing an amino moiety or a mono- or bicyclic heterocyclic moiety, R1 may inter alia be an arylsulfonyl group and R6 is selected from H, alkyl, aryl, halogen, hydroxy, alkoxy, amino, alkylamino and dialkylamino. Those compounds are used for the treatment of migraine related to the 5-HT1D receptor.
WO 2005/037834 discloses compounds of the following formula,
wherein  represents a single or double bond, P may inter alia be a substituted sulfonyl group, U is C or CH substituted by a group containing a nitrogen-containing moiety, which may be a heterocycle, W1, W2, W3, Y and Z are each a carbon or one of said variables is a nitrogen atom and Rm and Rm′ are selected from the group consisting of hydrogen, halogen, C1-C6-alkyl, hydroxy, C1-C6-alkoxy, C2-C6-alkenyl, phenyl, phenoxy, benzyloxy, benzoyl, —OCF3, —CN, C1-C6-hydroxyalkyl, C1-C6-haloalkyl, —NR2, —NO2, —CONR2, —NHSO2R, —NRCOR′, —SO2NRR′, —C(═O)R, C1-C6-alkoxycarbonyl, —S(O)eR, —SCF3, —CHF═CH2, —OCF2H and ethynyl. The compounds are mentioned to be useful for the treatment of 5-HT6 receptor-related disorders.
However, there is still an ongoing need for providing compounds having high affinity for the 5-HT6 receptor and which show high selectivity to this receptor. In particular the compounds should have low affinity to adrenergic receptors, such as 1-adrenergic receptor, histamine receptors, such as H1-receptor, and dopaminergic receptors, such as D2-receptor, in order to avoid or reduce considerable side effects associated with modulation of these receptors, such as postural hypotension, reflex tachycardia, potentiation of the antihypertensive effect of prazosin, terazosin, doxazosin and labetalol or dizziness associated to the blockade of the 1-adrenergic receptor, weight gain, sedation, drowsiness or potentiation of central depressant drugs associated to the blockade of the H1-receptor, or extrapyramidal movement disorder, such as dystonia, parkinsonism, akathisia, tardive dyskinesia or rabbit syndrome, or endocrine effects, such as prolactin elevation (galactorrhea, gynecomastia, menstruyl changes, sexual dysfunction in males), associated to the blockade of the D2-receptor.
It is an object of the present invention to provide compounds which have a high affinity and selectivity for the 5-HT6 receptor, thus allowing the treatment of disorders related to or affected by the 5-HT6 receptor.
The compounds should also have good pharmacological profile, e.g. a good brain plasma ratio, a good bioavailability, good metabolic stability, or a decreased inhibition of the mitochondrial respiration.